Plasma cells (PC), a defining feature of humoral immunity, secrete large amounts of protective antibodies. The lifespan of PCs can range from days to months, producing antibodies for either short (by shortlived PCs) or long (by long-lived PCs) duration. The mechanisms controlling the longevity of PCs during their genesis are not understood. These are fundamental issues relevant not only for development of antibody protection, but may also lead to new insights into vaccine design as well as the processes controlling pathogenic PCs in malignancies and antibody-mediated autoimmunity. A key to our understanding of long-lived PC differentiation came when my group defined a population of antigen (Ag)-stimulated post-germinal center B cells as precursors to long-lived PCs (PCpre). We demonstrated that, upon B cell encounter with T celldependent Ag and differentiation to PCpre, the PCpre within secondary lymphoid organs migrate to bone marrow (BM) where they persist long-term through self-renewal and give rise to long-lived PCs. Furthermore, we established that self-renewal of PCpre is required for them to become mature PCs, and that this process is dependent on the BM microenvironment. We have since moved forward to identify the signals within BM that control PCpre self-renewal and differentiation into long-lived PCs. New data provided in this application demonstrates that the long-term survival of PCs produced de novo from PCpre is controlled by interactions with the cytokines BLyS and IL-6. Furthermore, subsequent encounter of Ag by BM PCpre drives production of longlived PCs that secrete high-affinity antibodies. These preliminary findings suggest that self-renewal of PCpre and their differentiation into long-lived PCs are controlled by BLyS, IL-6, and Ag signaling within BM. In chronic inflammation, this process is abnormal. We have determined that both PCpre and PC populations survive over long periods of time in BM but also within secondary lymphoid organs in mice that develop chronic inflammation. These findings suggest that signals expressed in inflamed secondary lymphoid organs control accumulation of PCpre and PCs. Based on these exciting findings, we hypothesize that PCpre is the critical postgerminal center B cell population which migrates from the secondary lymphoid organs to the BM and, under the control of specific signals provided within the BM microenvironment, leads to the generation of long-lived PCs. We postulate that these signals, normally confined to the BM, are enabled in inflamed secondary lymphoid organs, leading to the abnormal development and survival of PCpre and their PC offspring within these tissues. In the proposed studies, our goal is to identify the factors that control development and maintenance of long-lived PCs using established wild-type, knockout, and congenic mouse models.